P-glycoprotein (PGP) is a protein found in cell membranes that acts as a powerful efflux pump, pushing foreign substances out of the cell. While this action is a fundamental part of the body’s natural defense system, it limits the effectiveness of many therapeutic drugs. PGP inhibitors are compounds designed to block this pump. By neutralizing PGP’s function, these inhibitors allow medications to remain inside target cells, offering a strategy for overcoming drug resistance and improving bioavailability.
The Role of P-glycoprotein in Cellular Defense
P-glycoprotein (MDR1) is an energy-dependent transporter belonging to the ATP-binding cassette (ABC) superfamily of proteins. Its primary function is actively extruding a wide variety of structurally diverse compounds out of the cell. This transport mechanism is powered by the hydrolysis of adenosine triphosphate (ATP), making it an active process requiring cellular energy.
PGP is strategically positioned in numerous tissues that form natural barriers against toxins. High concentrations are found in the intestines, limiting the absorption of ingested drugs into the bloodstream. It is also highly expressed in the kidney, liver (aiding in xenobiotic elimination), and the blood-brain barrier (protecting the central nervous system). This detoxification role becomes problematic when therapeutic drugs, such as chemotherapy agents, are recognized and rapidly ejected by the pump.
How PGP Inhibitors Block Drug Efflux
PGP inhibitors interfere with the pump’s ability to recognize and transport its substrates, leading to increased intracellular drug concentration. Inhibition falls into two categories: competitive and non-competitive modulation. Competitive inhibitors bind to the same site on the PGP molecule as the therapeutic drug, preventing the therapeutic agent from being recognized and extruded.
Non-competitive, or allosteric, inhibitors bind to a distinct site on the protein away from the substrate pocket. This binding causes an allosteric change in the PGP molecule’s shape, impairing the pump’s function or its ability to hydrolyze ATP. The result of both types of inhibition is the same: the efflux mechanism is blocked, allowing the therapeutic drug to accumulate inside the target cell.
Clinical Applications in Overcoming Drug Resistance
The main therapeutic use for PGP inhibitors is overcoming Multi-Drug Resistance (MDR), especially in cancer treatment. Many cancer cells develop resistance by overexpressing PGP, rapidly pumping out cytotoxic drugs before they can kill the cell. This PGP-mediated resistance causes chemotherapy failure, as the cancer becomes simultaneously resistant to multiple agents.
PGP inhibitors are used adjunctively to restore sensitivity to chemotherapy in drug-resistant tumors. Co-administering an inhibitor (e.g., Tariquidar or Zosuquidar) alongside a chemotherapy drug (e.g., Paclitaxel) deactivates the PGP pumps. This allows the chemotherapeutic agent to remain inside the malignant cell, increasing its concentration and enhancing tumor-killing efficacy.
PGP inhibition also improves the absorption of orally administered drugs outside of oncology. Many PGP substrates are poorly absorbed because the intestinal pump ejects them back into the gut lumen, reducing bioavailability. Temporarily inhibiting intestinal PGP increases the amount of drug that successfully crosses the gut barrier into the bloodstream. Research focuses on developing more specific and potent third-generation modulators to improve therapeutic outcomes.
Natural and Dietary Sources of PGP Modulators
Beyond synthetic drug development, compounds in foods and dietary supplements act as PGP modulators. These natural substances can either inhibit or induce PGP activity, which has implications for drug-drug interactions. For instance, certain flavonoids, which are plant pigments, can bind to PGP and inhibit its efflux activity.
Well-known dietary modulators include components from grapefruit juice (bergamottin and quercetin), which inhibit PGP and increase the oral absorption of co-administered substrate drugs. Curcumin (from turmeric) and piperine (from black pepper) are also identified as PGP inhibitors. Consuming these common foods or supplements alongside prescription medications can lead to unexpected increases in drug concentration, highlighting the importance of understanding PGP modulation for patient safety.